The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that senses diverse environmental cues, such as growth factors, cellular stresses, and nutrient and energy levels. When activated, mTORC1 phosphorylates substrates that potentiate anabolic processes, such as mRNA translation and lipid synthesis, and limits catabolic ones, such as autophagy. mTORC1 dysregulation occurs in a broad spectrum of diseases, including diabetes, epilepsy, neurodegeneration, immune response, suppressed skeletal muscle growth, and cancer among others (Howell et al., 2013; Kim et al., 2013; Laplante and Sabatini, 2012).
Many upstream inputs, including growth factors and energy levels, signal to mTORC1 through the TSC complex, which regulates Rheb, a small GTPase that is an essential activator of mTORC1 (Brugarolas et at, 2004; Garami et al., 2003; Inoki et al., 2003; Long et al., 2005; Sancak et al., 2008; Saucedo et al., 2003; Stocker et al., 2003; Tee et al., 2002). Amino acids do not appear to signal to mTORC1 through the TSC-Rheb axis and instead act through the heterodimeric Rag GTPases, which consist of RagA or RagB bound to RagC or RagD, respectively (Hirose et al., 1998; Kim et al., 2008; Nobukuni et al., 2005; Roccio et al., 2005; Sancak et al., 2008; Schumann et al., 1995; Sekiguchi et al., 2001; Smith et al., 2005). The Rag GTPases control the subcellular localization of mTORC1 and amino acids promote its recruitment to the lysosomal surface, where the Rheb GTPase also resides (Buerger et al., 2006; Dibble et al., 2012; Saito et al., 2005; Sancak et al., 2008). Several positive components of the pathway upstream of the Rag GTPases have been identified. The Ragulator complex localizes the Rag GTPases to the lysosomal surface and, along with the vacuolar-ATPase, promotes the exchange of GDP for GTP on RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010b; Zoncu et al., 2011). The distinct FLCN-FNIP complex acts on RagC/D and stimulates its hydrolysis of GTP into GDP (Tsun et al., 2013). When RagA/B is loaded with GTP and RagC/D with GDP, the heterodimers bind and recruit mTORC1 to the lysosomal surface, where it can come in contact with its activator Rheb GTPase.
Recent work has identified the GATOR1 multi-protein complex as a major negative regulator of the amino acid sensing pathway and its loss causes mTORC1 signaling to be completely insensitive to amino acid starvation (Bar-Peled et al., 2013; Panchaud et al., 2013). GATOR1 consists of DEPDCS, Npr12, and Npr13, and is a GTPase activating protein (GAP) for RagA/B. The GATOR2 multi-protein complex, which has five known subunits (WDR24, WDR59, Mios, Sec13, and Seh1L), is a positive component of the pathway and upstream of or parallel to GATOR1, but its molecular function is unknown (Bar-Peled et al., 2013).
The Sestrins are three related proteins (Sestrin1, -2 and -3) of poorly characterized molecular functions (Buckbinder et al., 1994; Budanov et al., 2002; Peeters et al., 2003). Sestrin2 inhibits mTORC1 signaling and has been proposed to activate AMPK upstream of TSC as well as interact with TSC (Budanov and Karin, 2008), but its mechanism of action remains undefined.
There is still a great need to better understand how amino acids modulate mTORC1 activity and to identify the crucial components mediating this modulation. Such components are potential therapeutic targets for selectively modulating mTORC1 activity indirectly.